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Low Temperature Plasma Applications in Medicine FEATURES LOW TEMPERATURE PLASMA APPLICATIONS IN MEDICINE 1 2 1 l K.-D. Weltmann , H.-R. Metelmann , Th. von Woedtke – DOI: http://dx.doi.org/10.1051/epn/2016507 l 1 Leibniz Institute for Plasma Science and Technology (INP Greifswald), Greifswald, Germany l 2 Greifswald University Medicine, Greifswald, Germany The main field of plasma medicine is the direct application of cold atmospheric plasma (CAP) on or in the human body for therapeutic purposes. CAP is effective both to inactivate a broad spectrum of microorganisms including multiple drug resistant ones and to stimulate proliferation of mammalian cells. Clinical application has started in the field of wound healing and treatment of infective skin diseases. Cold atmospheric plasma (CAP) is flowing through the tube. The plasma is ignited inside sources for medical application the device. The effluent is blown out along the gas flow A well-established field of atmospheric plasma applica- and can be brought into direct contact with the target tion is electro surgery where thermal plasma effects are to be treated. Several plasma jet devices are using noble used above all for coagulation and tissue cutting. In con- gases like helium or argon, but air or gas mixtures are trast, plasma medicine is focused actually on low temper- also useful as working gases. ature plasmas (< 40°C) to avoid thermal effects on living Independent on the basic principle of plasma gener- structures. Cold atmospheric plasma (CAP) sources for ation, all these atmospheric pressure plasmas are small medical application have to meet particular requirements. scale and filamentary and are generated inside small Such devices have to guarantee manageable, stable, relia- discharge gaps (p*d-scaling of breakdown voltage). The ble, and reproducible operation at low temperature and plasmas are non-uniform and constricted and consist open atmospheres. Besides a comprehensive characteri- of micro discharges or filaments, i.e. these are transient, zation of qualitative and quantitative plasma parameters short lived plasmas. and “macroscopic” characteristics especially a meaningful knowledge of biological performance is an essential pre- Biologically active plasma components requisite for both effective and safe medical application. and basic mechanisms of action During recent years, mainly three basic types of CAP In general, cold atmospheric pressure plasma is a mixture devices were tested and partially applied for medical pur- of reactive components including charged species (ions poses (Fig. 1) [1,2,3]. and electrons), excited neutral species mainly from the In the volume dielectric barrier discharge (DBD) plas- working gas, reactive oxygen and nitrogen species, visible, ma is ignited in the gap between an isolated high voltage ultraviolet (UV) and infrared (IR) radiation and other electrode and the target to be treated, i.e. in medical appli- electromagnetic fields (Fig. 2). Dependent on the indi- cation human tissue (e.g. skin or wound surface) is part vidual configuration of the plasma source, composition, of the discharge electrode configuration. In the surface relationship and quantity of these plasma compounds DBD, plasma is ignited around an individually designed may vary significantly. electrode structure (e.g. circular or grid-like) which is Based on a huge number of basic research using cul- isolated from a counter electrode. Both electrodes can tivated microorganisms and human cells [3], two main serve either as high voltage or ground electrodes. For basic principles of biological plasma action have been treatment of living tissue, the plasma has to be brought in identified recently: close vicinity of the target to be treated. With both DBD 1. Biological plasma effects are significantly caused by configurations, atmospheric air is usually the working gas. plasma induced changes of the liquid environment In a plasma jet device, the electrode setup for plasma of cells. generation is located usually in a capillary or tube-like 2. Reactive oxygen and nitrogen species (ROS, RNS) gen- arrangement in most cases inside a pen-like device. Di- erated in or transferred into liquid phases by plasma verse electrode configurations can be used, e.g. pin elec- treatment play a dominating role in biological plas- trodes, ring electrodes, plate electrodes etc. A working gas ma activity. EPN 47/5&6 39 FEATURES LOW TEMPERATURE plasma applications IN MEDICINE According to the actual knowledge, UV part of CAP The fundamental insight of the dominating role of has low or no direct biological effects because typically ROS and RNS was highly valuable because the large and low doses are emitted by plasma devices designated for well established field of redox biology now can serve as a medical use. However, its supporting role in reactive spe- sound scientific basis to explain biological effects of CAP. cies generation by photochemical activity has to be taken ROS and RNS regularly occur in cell biological processes - into consideration. (e.g. superoxide O2 •, hydrogen peroxide H2O2, hydroxyl 1 Electrical fields or current, respectively, reaching living radical •OH, singlet oxygen O2, nitric oxide •NO, nitro- - tissue is strongly dependent on type of discharge and gen dioxide •NO2 und peroxynitrite ONOO ). There- therefore might have varying direct biological effects. In fore, mammalian cells have protective mechanisms to this field, much more research is needed to finally enlight- save from reactive species concentrations going beyond en the role of this plasma compound for its direct part physiological levels. Such so-called oxidative stress might in biological and medically relevant plasma action but have severe consequences, e.g. genotoxic DNA changes. also for its role in the generation or support of action of However, detailed investigations using well-established other plasma compounds, above all of reactive species [4]. experimental procedures could demonstrate repeatedly However, the dominating role of ROS and RNS is estab- that detrimental plasma effects on cells in general and lished and demonstrated by several experimental setups particularly on DNA result either in cellular repair pro- independent on the specific plasma device used [5,6]. Gen- cesses or in induction of programmed cell death (apop- eration of ROS and RNS is mainly referable to atmospheric tosis) as a direct consequence. It has been demonstrated oxygen and nitrogen which are part of the working gas in that application of cold atmospheric plasma does not air-based plasma sources but is also admixed into the plas- cause increased risk for genotoxic effects [7,8]. ma in the case of noble gas-based plasma sources if they Three general biological plasma effects have been are working at open atmospheric conditions. According described repeatedly that are most relevant for medical to the actual state of knowledge, differences of biological application [3]: performance between plasma sources are mainly referred • its potential to inactivate a broad spectrum of microor- to quantities of ROS and RNS or its proportion of mixture ganisms including multidrug resistant ones in the respective plasma. However, possible role of UV • its potential to stimulate cell proliferation and conse- radiation or electric fields has to be kept in mind. quently to promote tissue regeneration m FIG. 1: Basic principles of cold atmospheric plasma (CAP) for biomedical research and medical application 40 EPN 47/5&6 LOW TEMPERATURE plasma applications IN MEDICINE FEATURES • its ability to inactivate mammalian cells and especially A highly topical field of basic and preclinical research m FIG. 2: With cold cancer cells by initialization of the programmed cell is CAP application in cancer therapy due to the fact that atmospheric plasma (CAP) a mixture of death (apoptosis) CAP can inactivate cancer cells by induction of the reactive components programmed cell death (apoptosis). Because these cells dominated by Medical application of CAP seem to be much more sensitive for CAP treatment com- reactive oxygen and Since 2013, first CAP sources got CE certification as med- pared to non-malignant cells it opens up new options of nitrogen species (ROS, RNS) is working ical devices. One of it is the argon-driven cold atmos- supportive CAP application e.g. in surgical or radiative on living tissue, e.g. pheric plasma jet kINPen MED (neoplas tools GmbH, cancer eradication as well as in palliative cancer thera- a wound. Wound Greifswald, Germany), which is based on comprehensive pies [12,13,14]. healing by plasma physical, biological, pre-clinical and clinical characteri- Possibilities of plasma application in dentistry include is a combination of inactivation zation [9,10]. Two other well-investigated medical CAP disinfection of tooth root canal, treatment of dental im- of bacteria and devices are the jet-like microwave-driven Ar-plasma plants both for biofilm removal and improvement of bone stimulation of tissue torch MicroPlasSter (ADTEC, Hunslow, UK) and the cell adherence and therapy of intraoral infections and regeneration. PlasmaDerm device (CINOGY GmbH Duderstadt, Ger- also wounds [15]. many) which is based on a volume DBD working with Besides these large fields of basic, pre-clinical and clin- atmospheric air [11]. ical research in plasma medicine, further fields of medical These plasma sources are certified mainly for the treat- plasma use, such as ophthalmology, cardiology, pneu- ment of chronic wounds as well as pathogen-based skin mology or plastic and aesthetic surgery are investigated.
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